The Aethera Trial: An Ongoing Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at High Risk of Residual Hodgkin Lymphoma Following Autologous Stem Cell Transplant

Background

Although autologous stem cell transplant (ASCT) can be curative for patients (pts) with relapsed/refractory Hodgkin lymphoma (HL), those with high-risk disease have long-term progression-free survival (PFS) of approximately 25% and could benefit from novel therapeutic approaches (Majhail 2006). Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE).  In a pivotal phase 2 study in pts with relapsed or refractory HL following ASCT, the objective response rate was 75%, with complete remissions (CR) in 33% of pts.  A phase 3 study was initiated to evaluate the potential of brentuximab vedotin to prevent relapse post-ASCT in pts at high risk of lymphoma progression (ClinicalTrials.gov #NCT01100502).

Methods

The AETHERA trial is a phase 3, randomized, double-blind, placebo-controlled, multicenter study.  After ASCT, pts received brentuximab vedotin 1.8 mg/kg q3wk and best supportive care (BSC) or placebo and BSC for up to 16 cycles (approximately 12 months).  The primary endpoint is PFS per independent review; additional endpoints include overall survival and safety/tolerability.  A planned interim safety and futility analysis was performed in Q4 2012; at that time 1214/1251 (97%) of the expected CT scans had been received for central independent review.

Patient Characteristics/Results

Protocol enrollment occurred from April 2010 through September 2012.  A total of 329 pts were enrolled and randomized; of these, 327 received study treatment.  Of the 327 pts, 133 (40%) were enrolled from the United States, 48 (15%) from Western Europe, and 146 (45%) from Central/Eastern Europe and Russia.  The median age was 32 years (range 18–76) and 52.6% were male.  Pts were enrolled in 1 of 3 high-risk categories: refractory to frontline therapy: 195 pts (59.6%), relapse <12 months after frontline therapy: 107 pts (32.7%), and relapse ≥12 months after frontline therapy with extranodal disease: 25 pts (7.6%).  Response to salvage pre-ASCT was CR: 122 pts (37.3%), PR: 112 pts (34.3%), and SD: 93 pts (28.4%).  Overall, 33% of pts were known to be PET-negative prior to ASCT.  ASCT conditioning regimens were carmustine, etoposide, cytarabine, and melphalan (BEAM; 61%), cyclophosphamide, carmustine, and etoposide (CBV; 11%), or other (28%) and included radiation in 6% of pts.  All pts were off treatment as of August 2013.  The median number of treatment cycles was 15 (range, 1-16) and 159 pts (49%) received 16 cycles.  A total of 61 pts (19%) discontinued treatment due to adverse events.   Thirty-five pts (11%) are known to have died; 31 deaths occurred after disease progression.  One death occurred within 30 days of last dose and was considered disease-related.

Conclusions:  Based upon a planned interim safety and futility analysis, the IDMC recommended that the AETHERA trial continue per protocol.